Chronic exposure to estrogen and the tobacco carcinogen NNK cooperatively modulates nicotinic receptors in small airway epithelial cells

Impact of Neuro-Psychological Factors on Smoking-Associated Lung Cancer

“…The release of the excitatory neurotransmitters norepinephrine, epinephrine, serotonin, dopamine and glutamate in the brain are regulated by the α7nAChR while the α4β2nAChR is primarily responsible for the regulation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain [26,28]. The neurotransmitters synthesized and released from epithelial cells and the cancers arising from them are similarly regulated, with the α7nAChR regulating serotonin [29,30] and jointly with the α3- and α5nAChRs epinephrine and norepinephrine [31,32,33] while the α4β2nAChR regulates GABA [33,34]. The expression of nAChRs with α subunits α1–α9 has been reported in normal airway and alveolar epithelium [16].…”

“…Instead, the majority of preclinical investigations have focused on the role of the α7nAChR in the regulation of lung cancer proliferation, metastatic potential, resistance to therapy and angiogenesis (reviewed in [19,21,35,36]). While most of these studies have interpreted the observed activation of intracellular signaling pathways as direct responses to α7nAChR activation by agonist, in vitro experiments with small airway epithelial cells [32], NSCLC cells [34], colon cancer cells [31] and pancreatic ductal adenocarcinoma cells and pancreatic duct epithelial cells [33,37] have established that these cancer-stimulating responses were caused by the α7nAChR-mediated synthesis and release of the stress neurotransmitters norepinephrine and epinephrine which activated multiple signaling cascades downstream of β-adrenergic receptors in an autocrine fashion. In accord with the concept that nAChRs are redundant [23,24,27], it has also been shown that nAChRs with subunits α3 and α5 contribute to the stress-neurotransmitter-induced proliferation and migration induced by nicotine in epithelial cancer cells [33].…”

“…In accord with the concept that nAChRs are redundant [23,24,27], it has also been shown that nAChRs with subunits α3 and α5 contribute to the stress-neurotransmitter-induced proliferation and migration induced by nicotine in epithelial cancer cells [33]. Moroever, it has been shown that small airway epithelial cells, NSCLC cells and pancreatic duct epithelial cells and the cancers derived from them express both isozymes of glutamate decarboxylase (GAD65, GAD67) that mediate the synthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) from glutamate and that they release GABA into the extracelullar environment [32,33,34]. …”

“…The release of the stress neurotransmitters norepinephrine and epinephrine from sympathetic nerves is thus regulated by the α7 nAChR and by nAChRs with subunits α3 and α5 in the adrenal gland. Epinephrine and norepinephrine in vitro stimulate cell proliferation and migration of cancer of the breast [38], colon [31,39], prostate [40], pancreatic ductal adenocarcinoma and pancreatic duct epithelia [33] and of lung adenocarcinoma and small airway epithelia [32,34]. By contrast, GABA in vitro has been shown to inhibit cell proliferation and migration of cancer of the breast [38], colon [41], pancreas [37,42] and lung adenocarcinoma [34,43].…”

“…By contrast, the nicotine-derived carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a preferential agonist for the α7nAChR to which it binds with approximately 1300× higher affinity than nicotine [12,13]. It has been shown that similar to nAChR responses to chronic nicotine in the brain associated with nicotine addiction, chronic exposure of small airway epithelial cells in vitro to NNK upregulates the protein expression of the α7nAChR and sensitized the receptor, resulting in increased release of norepinephrine and epinephrine in response to lower concentrations of NNK whereas chronic NNK desensitized the α4nAChR, suppressing GABA release [32]. Nicotine has been used extensively as a pharmacological tool to study the pathobiology of nAChRs as it relates to nicotine addiction and cancer.…”